PARANEOPLASTIC MANIFESTATIONS
OF LUNG CANCER
Paraneoplastic effects of tumors are remote effects that are not related
to direct invasion, obstruction, or metastases. Paraneoplastic syndromes occur
in 10% to 15% of all lung cancers. The following are some of the most common.
The syndrome of inappropriate antidiuretic hormone
secretion (SIADH) may be caused by pulmonary infections, central nervous system
(CNS) disease or trauma, drugs, or lung tumors. Small cell lung cancer is the
most common malignancy to cause SIADH. The tumor secretes ectopic antidiuretic
hormone (ADH; vasopressin), which exerts its action on the kidneys and enhances the flow of water from
the lumen of the renal collecting ducts to the medullary interstitium with
resulting concentration of the urine. Patients present with hyponatremia that
is associated with low plasma osmolality and elevated urine sodium and
osmolality. To make the diagnosis of SIADH, patients must also have normal
renal, adrenal, and thyroid function. The symptoms of hyponatremia may include
anorexia, nausea, vomiting, irritability, restlessness, confusion, coma, or
seizures. The severity of symptoms is related to the degree of hyponatremia and
the rapidity of the decrease in serum sodium. The treatment for mildly
symptomatic patients is to restrict fluid intake to 500 to 1000 mL/24 hours. For
more severe or life-threatening symptoms, treatment consists of intravenous
fluids with normal saline and loop diuretics. For severe symptoms, some experts
recommend 300 mL of 3% saline intra-venously, but extreme caution must be used
because too rapid correction of serum sodium may be associated with central
pontine myelinolysis, which is a devastating CNS process that is often fatal.
For patients with less severe symptoms from hyponatremia but requiring more
than fluid restriction, oral demeclocycline can be used. The onset of action may
take from a few hours to a few weeks, and renal function should be monitored.
The best treatment for SIADH, if the patient is stable, is to treat the small
cell lung cancer with systemic chemotherapy. Regression of the tumor results in
nor- malization of the sodium in most cases.
Cushing syndrome may be related to ectopic production
of corticotropin (adrenocorticotropic hormone) or corticotropin-releasing
hormone by small cell carcinoma. It has also been reported with bronchial
carcinoid tumors or carcinoid tumors of the thymus or pancreas. Small cell lung
cancer accounts for 75% of all cases of Cushing syndrome caused by ectopic
hormone secretion. Because of the rapid growth of small cell lung cancer,
patients are more likely to present with edema, hypertension, and hyperglycemia
with or without muscle weakness. This is in contrast to the classic features of
Cushing syndrome that include truncal obesity, rounded (moon) facies, buffalo
hump (dorsocervical fat pad), and diabetes mellitus. The best screen for
Cushing syndrome caused by ectopic hormone secretion is the 24-hour urine free
cortisol measurement. Marked elevation of cortisol production and plasma
corticotropin levels are highly suggestive of ectopic corticotropin as the
cause of Cushing syndrome.
Treatment of patients with ectopic corticotropin
production includes metyrapone, aminoglutethimide, mitotane, or ketoconazole
given alone or in combination. Ketoconazole is the most commonly used agent. If
the patient is stable with no superimposed infection, then systemic chemotherapy is the best treatment for
histologically confirmed small cell lung cancer. If the Cushing syndrome is
caused by carcinoid tumor, then surgical resection, if possible, is the
treatment of choice. Hypercalcemia in relation to lung cancer may be caused by
bone metastases, or less commonly, secretion of parathyroid hormone–related
protein (PTHrP) or other cytokines. The most common cancers to cause
paraneoplastic hypercalcemia are kidney, lung, breast, myeloma, and lymphoma.
For lung cancers, squamous cell carcinoma is the most common cell type
associated with hypercalcemia. Symptoms of hypercalcemia include anorexia,
nausea, vomiting, constipation, lethargy, polyuria, polydipsia, and
dehydration. Confusion and coma are late manifestations. A shortened QT
interval on electrocardiography, ventricular arrhythmia, heart block, and
asystole may occur. Renal failure and nephrocalcinosis are also possible.
Elevated PTHrP levels may be detected in the serum of about half of patients with hypercalcemia of malignancy that is not
caused by bony metastasis. Patients with mild elevation of calcium do not
require treatment. Treatment is determined by symptoms and includes intravenous
fluids to correct dehydration caused by polyuria and vomiting. Intravenous
treatment with bisphosphonates inhibits osteoclast activity, and one dose
achieves a normal calcium level in 4 to 10 days in most individuals. If rapid
partial correction of hypercalcemia is needed, calcitonin will rapidly lower
the calcium level by 1 to 2 mg/dL, but the effects are short lived. If the lung
cancer is localized, then the treatment of choice, after the patient has been
stabilized, is surgical resection. However, the usual situation is that the
patient has metastatic disease. For these individuals with hypercalcemia, the
average life expectancy, even with treatment, is 1 month.
Paraneoplastic neurologic syndromes (PNSs) are most
commonly associated with small cell lung cancer and are quite variable. They include Lambert-Eaton myasthenic syndrome
(LEMS), sensory neuropathy, encephalomyelopathy, cerebellar degeneration, autonomic
neuropathy, retinal degeneration, and opsoclonus. Limbic encephalitis (dementia
with or without seizures) has frequently been observed. The neurologic
syndromes may precede the diagnosis of lung cancer by months to years.
PNSs are thought to be immune mediated on the basis of
identifying autoantibodies. The antineuronal nuclear antibody (ANNA-1), also
known as anti-Hu antibody, has been associated with small cell carcinoma and
various neurologic syndromes. ANNA-2 (anti-Ri antibody) and CRMP-5 antibody
have also been associated with various PNSs. These antibodies predict the
patients’ neoplasm but not a specific neurologic syndrome. The ANNA-1 binds to
the nucleus of all neurons in the central and peripheral nervous system,
including the sensory and autonomic ganglia and myenteric plexus.
Proximal muscle weakness, hyporeflexia, and autonomic
dysfunction characterize LEMS. Cranial nerve involvement may be present and
does not differentiate LEMS from myasthenia gravis. There is a strong
association of LEMS with antibodies against P/Q type presynaptic voltage-gated
calcium channels of the peripheral cholinergic nerve terminals. These
antibodies have also been identified in 25% of patients with small cell lung
cancers with no neurologic syndrome. Myasthenia gravis, in contrast to LEMS, is
associated with antiacetylcholine receptor antibodies. Malignancy is identified
in approximately 50% of patients with LEMS, and small cell lung cancer is by
far the most common type. The diagnosis of LEMS is based on the characteristic
electromyographic (EMG) finding that shows a small amplitude of the resting
compound muscle action potential and facilitation with rapid, repetitive, and
supramaximal nerve stimulation. A single-fiber EMG is optimal for making the
diagnosis. Careful radiographic evaluation of the lungs and mediastinum is
indicated, especially in current or former smokers who have a suspected PNS. In
many cases, the radiographic findings are very subtle. If the patient has a
positive paraneoplastic autoantibody blood test result and the computed tomography
(CT) chest scan does not reveal an abnormality, then current guidelines
recommend that a positron emission computed tomography (PET) scan be performed
to look for an occult malignancy. Strong consideration should be given to
biopsy of even subtle abnormalities because without diagnosis and treatment the
PNS will progress, frequently with devastating consequences.
The best treatment for patients with PNS caused by
small cell lung cancer is to treat with chemotherapy with or without thoracic
radiotherapy, depending on the stage of disease. LEMS may improve with
treatment, but not always. The other PNSs rarely improve with treatment, but
the goal is to treat the lung cancer as soon as possible to try to prevent
progressive neurologic disease.
Skeletal muscular paraneoplastic syndromes include
digital clubbing, hypertrophic pulmonary osteoarthropathy (HPO), and
dermatomyositis or polymyositis. Clubbing may involve the fingers and toes and consist of selective enlargement of the connective
tissue in the terminal phalanges with loss of the angle between the base of the
nail bed and cuticle, rounded nails, and enlarged fingertips. There are
nonmalignant causes of clubbing such as pulmonary fibrosis or congenital heart
disease. HPO is uncommon in association with lung cancer and is characterized
by painful joints that usually involve the ankles, knees, wrists, and elbows
and is most often symmetric. Some patients may complain of pain or tenderness
along the shins. The pain and arthropathy is caused by a proliferative
periostitis that involves the long bones but may involve metacarpal,
metatarsal, and phalangeal bones. Clubbing may be present along with HPO. Large
cell and adenocarcinoma are the most common types to cause HPO. The cause of
HPO is uncertain but is thought to be attributable to a humeral agent. A
radiograph of the long bones (tibia and fibula or radius and ulna) may show the
characteristic periosteal new bone formation. An isotype bone scan or PET scan typically demonstrates diffuse uptake in the long
bones. Symptoms of HPO may resolve with thoracotomy with or without resection
of the malignancy. For inoperable patients, treatment with nonsteroidal
anti-inflammatory agents is often of benefit. Recently, the use of intravenous
bisphosphonates has been reported to alleviate the symptoms of HPO.
There have been reports of the association of lung
cancer with dermatomyositis-polymyositis (DM-PM), but the relationship is
uncertain. Patients may present with painful muscles and weakness. Blood tests
for the muscle enzymes creatine kinase or aldolase will demonstrate elevated
levels. An EMG or muscle biopsy is diagnostic. A CT scan of the chest is
warranted in a patient with DM-PM who is at high risk for lung cancer. The
treatment of patients with malignancy-related DM-PM is the same as for non malignancy related disease plus a propriate treatment of the underlying lung cancer.
